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Published in final edited form as: Mater Today Chem. 2021 Jan;42:29–40. doi: 10.1016/j.mattod.2020.10.007

Modulation of physical properties of organic cocrystals by amino acid chirality

Wei Ji 1, Bin Xue 2, Santu Bera 1, Sarah Guerin 3, Linda JW Shimon 4, Qing Ma 5, Syed AM Tofail 3, Damien Thompson 3, Yi Cao 2, Wei Wang 2, Ehud Gazit 1,6,*
PMCID: PMC7617027  EMSID: EMS117036  PMID: 39649477

Abstract

Amino acid chirality plays an important role in conveying directionality and specificity to their supramolecular organization. However, the impact of enantiopure and racemic amino acids on the favorable packing and macroscopic properties of organic cocrystals with nonchiral coformers is poorly understood. Herein, we performed a systematic study of the effect of chirality on the macroscopic properties of acetylated alanine (AcA) single crystals and cocrystals with a nonchiral photo-sensitive bipyridine derivative (BPE). Cocrystallization with BPE produced a marked morphology transition that improved the supramolecular chirality, thermal stability and mechanical strength of AcA crystals. The distinct supramolecular packing modes were analyzed by X-ray crystallography. The highest rigidity was observed for BPE/DL-ACA, WHILE BPE/D-ACA AND BPE/L-ACA crystals exhibited higher efficiency of photo-induced emission for fluorescent imprinting, as well as significantly higher piezoelectricity. This work provides a striking illustration that subtle differences in amino acid stereochemistry translate into tunable macroscopic properties of organic cocrystals for future applications in rigid solids, fluorescent imprinting, and energy harvesting.

Introduction

Chirality is one of the most distinctive natural attributes of biomacromolecules. A fundamental design rule observed in all living organisms is that only L-amino acids are incorporated into proteins and enzymes and only D-sugars (deoxyribose and ribose) form the backbones of DNA and RNA, which plays an important role in chemistry, physics, biology, and medicine [1–5]. Chirality is well understood at the molecular level but systematic investigations of how molecular chirality influences bottom-up organization processes, which are crucial for rational design of supramolecular structures and devices for nanotechnology, are still scarce [6–19]. Over the past decade, much effort has been devoted to investigate the chirality transfer of amino acids and peptides into supramolecular aggregates at nano-scale dimension, which can be translated into macroscopic differences in materials behavior [20–28]. The incorporation of D-amino acids into small peptides not only changes the geometry of the molecules, but also modulates the nanoscopic properties of their supramolecular assemblies, including morphology [29], thermal stability [30], mechanical strength [31,32], and biological activity [33–35]. For example, amino acid chirality has been widely regarded as a key factor to produce left-handed and righthanded nanostructures by controlling the handedness of their folding and supramolecular organization [36,37], and the supramolecular chirality of nanofibrils has been reported to regulate cell adhesion and proliferation behaviors in three dimensional (3D) extracellular matrix environments [38,39].

To extend this approach for minimal building units, recent studies have shown that racemic amino acids significantly modulate the properties of their supramolecular assemblies, compared to those of the pure enantiomers. The transition of L- phenylalanine amyloid fibrils into flakes with higher rigidity was observed upon addition of the D-enantiomer, a change that may inhibit amyloid formation in phenylketonuria disease [40,41]. In other examples, a pyroelectric effect was demonstrated using nonpolar crystals of L-alanine doped with the opposite enantiomer due to an interchange of enantiomers at specific chiral crystal sites [42,43]. Similarly, compared to the pure L enantiomer, a twofold higher piezoelectric power generation was achieved using DL-alanine crystal films under simple manual compression [44]. However, the effect of amino acid chirality on the macroscopic properties of cocrystals with achiral coformers is still largely unexplored, possibly because the criteria for cocrystal formation are quite restrictive [45]. As shown below, deeper understanding of the chirality effect may provide new coassembly strategies and opportunities for materials design and development.

Herein, we explored the effect of amino acid chirality on the macroscopic properties of both single and cocrystals, including morphology, thermal stability, mechanical strength, photoresponsiveness, and piezoelectricity. The pure form of acetylated alanine (either L-ACA or D-ACA) and 1,2-bis(4-pyridyl)ethylene (BPE) can form intermolecular hydrogen bonds between carboxylic acid and pyridine moieties [46], which may facilitate the formation of cocrystals (Fig. 1a). Furthermore, molecular BPE can undergo a trans–cis transition under UV light irradiation and emit enhanced fluorescence (Fig. 1b) [47,48]. The coassembly of AcA and BPE was fully characterized using fluorescence microscopy, power X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR). As described herein, while pure D-ACA and L- AcA crystallized as plates and racemic DL-ACA formed fractal crystals, co-assembly with BPE produced needle shapes with improved thermal stability. Notably, we were able to determine all the crystal structures of single and cocrystals with different chirality by X-ray crystallography, which revealed a similar packing for pure forms but a completely different organization for racemic mixtures (Fig. 1c and d). These differences in the packing modes resulted in markedly different properties of the crystals (Fig. 1e). First, atomic force microscopy (AFM) nanoindentation experiments suggested that DL-ACA exhibited higher Young’s modulus and point stiffness than the pure D- and L-isomer in both single and cocrystals, with the most rigid BPE/DL-ACA cocrystal showing high Young’s modulus (53.4 ± 4.9 GPa) and point stiffness (353.8 ± 12.8 N m-1) values. Second, due to the much stronger π-π stacking of BPE, the BPE/D-ACA and BPE/L-AcA cocrystals exhibited enhanced UV light-sensitivity and higher efficiency of photo-induced emission for fluorescent imprinting. Third, the BPE/D-ACA and BPE/L-ACA cocrystals showed higher calculated piezoelectric coefficients due to lower shear stiffness induced by the porous cocrystal structure, combined with modest piezoelectric polarization. These results demonstrate chirality-induced tunable macroscopic properties of single and multiple component crystals formed by very simple molecules, suggesting these assemblies as attractive materials for nanotechnology.

Figure 1.

Figure 1

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(a) Chemical structures of enantiopure L-AcA and D-AcA. (b) Photo-induced enhanced emission of BPE after trans-cis transition. (c) Molecular packing of enantiopure L-AcA and D-AcA, and their cocrystals with BPE. (d) Molecular packing of racemic DL-ACA, and its cocrystals with BPE. (e) Tunable macromolecular properties of single crystals and cocrystals, including mechanical strength, photo-sensitivity, and piezoelectricity.

Results and discussion

Co-assembly of BPE and chiral AcA

To explore the effect of chirality on the molecular packing and properties of both single and cocrystals, we selected the simple non-aromatic acetylated amino acid AcA, and studied its cocrystallization with the non-chiral photo-sensitive aromatic molecule BPE. Based on the affinity of intermolecular hydrogen bonding between the carboxylic acid group of AcA and the pyridine of BPE, the two simple molecules were expected to coassemble and produce different molecular arrangements by tuning the chirality of AcA. All samples were dissolved in methanol and slowly evaporated to generate crystalline solids at room temperature. The chosen molar ratio of BPE/AcA (1:2) in the coassemblies reflected the number of pyridine and carboxylic acid groups in BPE and AcA, respectively. We first checked the self- assembled morphology formed by the pure enantiomers of AcA and their mixed systems. A plate-like crystal shape was observed for D-ACA and L-ACA by fluorescence microscopy (Fig. 2a and Fig. S1a). However, the racemic mixture of DL-ACA formed fractal-shaped crystals (Fig. 2b), indicating the co-assembly of D-ACA with L-ACA. On the other hand, BPE self-assembled to form irregularly shaped crystals, which could emit green fluorescence under blue light excitation due to the conjugated aromatic nature of BPE (Fig. 2c and d). Distinct needle-shaped crystals with green emission were observed for all three co-assemblies, namely BPE/D-ACA, BPE/L-ACA, and BPE/DL-ACA, with the different morphology indicating the co-assembly of AcA with BPE (Fig. 2e-h and Fig. S1b-c). PXRD confirmed the co-assembly of the enantiomeric DL system in the presence or absence of BPE. Compared to pure D- and L-ACA, the appearance of new peaks (10.92°, 21.96°, 24.02°, 33.29°) and the absence of several original peaks (11.39°, 23.00°, 24.50°, 27.68°) was observed in the mixture of DL-ACA, indicating the new molecular arrangement and coassembly of racemic DL-ACA (Fig. 2i). Similarly, in the two components of AcA and BPE, the presence of several characteristic peaks of both individual AcA and BPE crystals along with the appearance of new peaks indicated the formation of BPE/D-AcA, BPE/L-ACA, and BPE/DL-ACA co-assemblies (Fig. S2a-c). While BPE/L-AcA and BPE/D-AcA showed very similar diffraction patterns, the observed right-shift of the two main peaks (12.13°, 24.41° to 12.61°, 25.43°) suggested a packing transition in the enantiomeric BPE/DL-ACA system (Fig. 2j).

Figure 2.

Figure 2

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(a and b) Microscopy images of D-AcA (a) and DL-ACA (b) crystals. (c-h) Fluorescence microscopy images of BPE (c, d), BPE/D-ACA (e, f), and BPE/DL-ACA (g, h) in bright field and UV excited channel. (i) PXRD of the D-AcA, L-ACA, and DL-ACA crystals. (j) PXRD of the BPE/D-ACA, BPE/L-ACA, and BPE/DL-ACA crystals. (k) Thermal stability of AcA-based single and cocrystals. (l) CD spectra of AcA-based single and cocrystals. (m) Amide A band and (n) amide I band of FTIR spectra of the D-AcA, BPE, and BPE/D-ACA crystals. (o) 1H NMR spectra of D-AcA, BPE, and BPE/D-ACA in D2O. (p) Chemical shift of 1H NMR of BPE/D-ACA, compared to the single components.

The thermal stability of the self- and co-assemblies was studied by thermogravimetric analysis (TGA) (Fig. 2k and Fig. S3). Compared to pure D-ACA (169.5 °C), pure L-ACA (169.0 °C), and racemic DL-ACA (177.3 °C), higher thermal stability was observed for the co-assemblies (197.4 °C, 184.5 °C, 195.0 °C for BPE/D- AcA, BPE/L-ACA, BPE/DL-ACA, respectively). These findings suggest that co-assembling with the more thermally stable BPE coformer (191.4 °C) produces a new packing mode that improves the thermal stability relative to pure AcA. Amino acid chirality controls the geometry of molecules and their supramolecular organization, affecting the supramolecular chirality of assemblies [36,37]. Furthermore, the supramolecular chirality of all crystal samples was evaluated by CD spectra since (Fig. 2l). The single crystals did not show any obvious chirality signals, but the co-assembled crystals exhibited a significant Cotton effect and strong ellipticity. The strong CD signal comes from the asymmetric supramolecular organization of BPE/AcA molecules, inducing supramolecular chirality. The different peak positions of the coassembled crystals reflect the different supramolecular packing regulated by the chirality of the amino acids, indicating that the co-assembly strategy improves the chiral response of the individual self-assemblies of AcA.

FTIR spectroscopy and 1H NMR spectra of crystal powders were analyzed to characterize the intermolecular hydrogen bonding interactions between the carboxylic acid of AcA and the pyridine of BPE during co-assembly. In the amide A band of FTIR, the peak of the N-H stretching vibration of the amide in D-ACA at 3328 cm-1 became weak and shifted to 3301 cm-1 after coassembling with BPE, indicating the change of interactions (Fig. 2m). In the amide I region, the peak at 1704 cm-1 ascribed to the C=O stretching vibration of the carboxylic acid in D-AcA disappeared and a new peak appeared at 1660 cm-1, indicating the formation of intermolecular hydrogen bonding between carboxylic acid and pyridine in the BPE/D-ACA co-assembly (Fig. 2n).

Similar shifting of FTIR peaks in the amide A and I regions was observed for crystals of L-ACA (3330, 1704 cm-1) and DL-ACA (3343, 1717 cm-1) versus BPE/L-ACA (3298, 1660 cm-1) and BPE/DL-ACA (3288, 1660 cm-1), respectively (Fig. S4). The chemical shifts of hydrogen atoms were evaluated to detect the intermolecular hydrogen bonding interactions between BPE and AcA. The labels of hydrogen atoms in the chemical structures of BPE (Ha, Hb, Hc) and AcA (Hd, He, Hf) are shown in Fig. S5 for analysis of 1H NMR experiments. In the co-assembly state of BPE/D-ACA (Fig. 2o and p), an obvious downfield shift was observed for all hydrogen atoms of BPE, while an upfield shift was found for the hydrogen atoms (Hd, Hf) of AcA close to the carboxylic acid group. Similar results were observed for BPE/L-ACA and for BPE/DL-ACA (Fig. S6). These results confirmed the intermolecular hydrogen bonding between the carboxylic acid and pyridine as the main enthalpic driving force for the co-assembly of AcA with BPE.

Crystal structures of AcA with different amino acid chirality To understand the molecular arrangement of the pure and racemic crystals at the atomic level, diffraction quality single crystals were grown from methanol and their structures were thoroughly analyzed. Detailed crystal data collection and refinement parameters of D-ACA and DL-ACA are summarized in Table S1. The crystal packing mode of L-ACA crystals in this study was found to be the same as the previously reported L-ACA crystal structure due to the identical PXRD patterns (Fig. S7) [49]. As expected, L-ACA and D- AcA produced similar unit cell parameters and mirrored higher order packing geometries (Fig. 3a and b). AcA crystallized in orthorhombic P212121 space group with one molecule per asymmetric unit, without inclusion of any solvent molecule in the asymmetric unit (Fig. 3a and b, Fig. S8a and S9a). The AcA molecule interacted with four adjacent molecules via H-bonds through both terminal acid and internal amide groups. The head-to-tail H-bonded connection of the molecules produced a zigzag molecular chain in the crystallographic a-direction (Fig. S8b and S9b). The molecular chains further connected in the c-axis to generate two-dimensional sheets (Fig. S8c and S9c). In terms of higher order packing, pure L-AcA and D-AcA crystals showed supramolecular helical structures (Fig. 3a and b). By contrast, the racemic DL-ACA crystallized with four molecules per asymmetric unit, comprising three D-AcA molecules and one L-ACA molecule, in monoclinic P21/c space group (Fig. 3c, Fig. S10). Two molecules of the same handedness (Lor D) were connected via face-to-face H-bonding interaction to produce a stable homomeric dimer structure (Fig. 3d). A single dimeric unit interacted with four adjacent dimers of opposite chirality to produce a 2D sheet-like molecular architecture (Fig. 3d). In higher order packing, these sheet-like modules further stacked one on the other by a 21 screw operation (Fig. 3e and f). This structural pattern of racemic DL-ACA is completely different from the packing of the enantiopure L-AcA and D-AcA.

Figure 3.

Figure 3

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(a and b) Asymmetric unit and higher order crystal packing of L-AcA (a) and D-AcA (b). (c-f) Crystal structure of DL-ACA: asymmetric unit (c), single molecular sheet composed of dimeric unit (d), and top-down stacking of adjacent 2D sheets (e and f). The carbon atoms of L and D-AcA are colored in green and purple, respectively. Nitrogen and oxygen heteroatoms are designated in blue and red, respectively.

Cocrystal structures of BPE/AcA with different amino acid chirality

To understand the atomic level interactions between BPE and different isomers of AcA and the resulting modulation of supramolecular structures compared to the individual components, diffractable cocrystals were grown and thoroughly analyzed. Detailed crystal data collection and refinement parameters of BPE, BPE/L-AcA, BPE/D-AcA, and BPE/DL-AcA are summarized in Table S1 and S2. Pure BPE crystallized with one water molecule in orthorhombic space group Pna21 (Fig. 4a, Fig. S11). In the solid-state structure of current crystal, the molecule adopted a stable trans conformation, with a dihedral angle between the pyridine rings of 20.3°. The N atoms of two adjacent pyridine rings connected by H-bonds via water, N1⋯H1Q–O1 and O1–H1P ⋯ N2, to construct a continuous 1D molecular chain in the crystallographic b direction (Fig. S12). Fig. 4b shows the higher order packing pattern of the BPE crystal. The structure exhibits no face-to-face π-π stabilization between aromatic rings as the shortest distance (7.609 Å) is too long to impart any considerable effect (Fig. 4c). Instead, several edge-to-face aromatic stacking interactions (distance 3.667 Å) and van der Waals contacts stabilized the neighbor molecular chains and held the three-dimensional supramolecular hydrogen-bonding network (Fig. 4d). Important structural parameters and H-bonding distances are compared for different pure BPE crystal structures in Supplementary Table S3. The current structure shows close similarity with an earlier reported crystal structure of BPE grown in ethanol/water (3:1) (Table S3). The structural pattern is significantly different from previously reported crystals of pure BPE grown in non-aqueous environment, in which no H-bonding stabilization was observed due to the absence of crystal waters (Fig. S13). These structures were stabilized through edge-to-edge or face-to-face aromatic-aromatic interactions. When BPE crystals were grown in the presence of L-AcA, one molecule of BPE crystallized with two molecules of L-AcA and one molecule of water in orthorhombic space group P21212 (Fig. 4e, Fig. S14). The stable trans conformation of the BPE molecule was preserved in the cocrystal, and L-AcA formed a strong dimer stabilized through two intermolecular H-bonds (N3-H3⋯O6 and O3⋯H4A–N4, Fig. 4f). This newly formed dimer acted as the bridge to connect two nearby BPE molecules through H-bonds (O5–H5A⋯N2 and O2–H2A⋯N1), similar to the water- mediated contacts in the crystal structure of pure BPE, to generate a 1D undulating molecular chain running in the crystallographic c direction (Fig. S15a). Two neighboring molecular chains were positioned in parallel and stabilized through van der Waals interactions (Fig. S15b). In addition, the chains interacted in a crisscross fashion producing an overlap of aromatic rings (Fig. S15c). When viewed along the b axis, the higher order packing of the cocrystal showed a layer-by-layer arrangement with one layer composed of BPE molecules and the next containing L-ACA dimers (Fig. 4g, Fig. S15d and S15e). In this packing mode, the interactions between nearby BPE molecules differ remarkably differed from those observed in the pure BPE structure. The stabilization through two types of partial face-to-face aromatic interactions identified in the structure was absent in pure BPE. In the first case (highlighted in blue, Fig. 4g), the two nearby BPE molecules slipped to produce a head-to-tail configuration in which the center-to-center distance between two closest pyridine rings was 3.588 Å (Fig. S15f). In the other case (highlighted in red, Fig. 4g), the adjacent BPE molecules rotated into a cross-stacking mode of packing, resulting in stabilization through a 3.811 Å center-to-center distance between overlapping pyridine rings (Fig. S15g). The molecular interactions and crystal packing observed in the BPE/D-AcA cocrystal was exactly similar to that of BPE/L-ACA with an analogous aromatic stacking pattern comprising a center-to-center distance of 3.591 Å and 3.808 Å, respectively (Figs. S16 and S17). Crystal structure analysis shows the molecular chains formed by BPE/D-ACA and BPE/L-ACA packing in a mirror image symmetry (Fig. S18), leading to the mirror imaged CD signals. By contrast, the cocrystal of BPE/DL-AcA showed a completely different supramolecular organization (Fig. 4h and i, Fig. S19 and S20). L-AcA and D-AcA separately interacted with BPE to fabricate two different molecular chains, one composed of BPE/L-AcA and the other one of BPE/D-AcA (Fig. S20a). There was no H-bond connection between these two enantiomeric 1D chains which were stacked around a 21 screw axis. In the higher order packing, each individual isomer formed a layer-by-layer arrangement with BPE (Fig. 4h, Fig. S20b and c). However, due to overlap of two different layer organizations, the overall packing pattern of BPE/DL-AcA displayed a complex 3D supramolecular network structure. In this packing organization, the aromatic interactions were modulated due to steric interference caused by crowding of molecules compared to their enantiopure cocrystals. Three types of aromatic interactions were observed between BPE molecules, two via head-to-tail stacking with a comparable centroid-centroid separation of 3.630 Å and the third through a partial edge-to-edge interaction with a large 4.878 Å centroid-to-centroid separation (Fig. 4i, Fig. S20d and f).

Figure 4.

Figure 4

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(a-d) Single crystal structure of BPE: (a) Asymmetric unit, (b) Higher order molecular packing in the crystallographic c direction, (c) The distance of face-to-face aromatic interaction and (d) Stabilization through edge-to-face aromatic interactions. (e-g) Cocrystal structure of BPE/L-ACA: (e) The asymmetric unit, (f) Intermolecular H-bonded connection between the L-AcA dimer and BPE, (g) Higher order layer structure with characteristic aromatic interactions between adjacent BPE units. (h-i) Cocrystal structure of BPE/DL-ACA: (h) Molecular organization of BPE, L-AcA and D-AcA molecules in the higher order packing, (i) Coexistence of two similar molecular architectures, one composed of BPE/L-ACA and the other comprised of BPE/D-ACA. The modulated aromatic interactions between the BPE molecules present in the structure are highlighted and enlarged images are shown. The carbon atoms of BPE, L-AcA and D-AcA are colored in gray, green and purple respectively. Nitrogen and oxygen heteroatoms are designated in blue and red respectively.

Mechanical properties of the single and cocrystals

AFM based nanoindentation experiments were performed to study the effect of amino acid chirality on the mechanical properties of both single and cocrystals [50]. The AFM cantilever tip was forced to press the surface of crystal samples deposited on a mica substrate and retracted at a constant speed of 80 pm s-1(Fig. S21-22). Then, the force-displacement traces obtained using the quantitative imaging (QI) mode of the probe allowed the Young’s moduli to be determined using the Hertz model (Fig. S23). The Young’s moduli for the pure crystals of D-ACA (Fig. 5a) L-ACA (Fig. S24a), and the racemic mixture of DL-ACA (Fig. 5b) were shown in topographic Young’s modulus maps. As further analyzed by the histogram distribution of Young’s modulus, the statistical values of Young’s modulus along the thickness direction were found to be 10.5 ±0.7 GPa (Fig. 5c), 10.7 ±1.1 GPa (Fig. S24b), and 19.7 ±6.4 GPa (Fig. 5d) for D-AcA, L-ACA, and DL-ACA, respectively. Moreover, the point stiffness could also be calculated according to the force-displacement traces. The statistical point stiffness values of the amino acid crystals were 132.4 ± 12.2 N m-1 (Fig. 5e), 142.6 ± 11.7 N m-1 (Fig. S24c), and 230.5 ± 36.9 N m-1 (Fig. 5f) for D-ACA, L-ACA, and DL-ACA, respectively. The elevated Young’s modulus and point stiffness of the racemic DL-ACA crystals indicated higher mechanical strength compared to the pure D-ACA and L-ACA crystals, further suggesting that the crystal network in racemic DL- AcA was more tightly-packed. Due to the relatively weak supramolecular packing, the Young’s modulus and point stiffness values of the BPE crystal were found to be 5.5 ± 1.1 GPa and 119.4 ± 14.7 N m-1, respectively (Fig. S24d and f). After coassembly with BPE, the effect of amino acid chirality on the mechanical properties of the cocrystals was also studied. The Young’s moduli for the pure cocrystals of BPE/D-ACA (Fig. 5g) and BPE/L-ACA (Fig. S24g), as well as the racemic cocrystal of BPE/DL-ACA (Fig. 5h), were also shown in topographic Young’s modulus maps. The statistical peak values of Young’s modulus for the cocrystals were found to be 28.8 ± 9.6 GPa (Fig. 5i), 24.2 ± 3.8 GPa (Fig. S24h), and 53.4 ±4.9 GPa (Fig. 5j) for BPE/ D-ACA, BPE/L-ACA, and BPE/DL-ACA, respectively. The corresponding statistical point stiffness values of the cocrystals were found to be 257.3 ± 35.9 N m-1 (Fig. 5k), 242.0 ± 24.6 N m-1 (Fig. S24i), and 353.8 ± 12.8 N m-1 (Fig. 5l), respectively. These results demonstrate the rigidity order to be [DL-ACA > (D or L)- AcA] and [BPE/DL-ACA > BPE/(D or L)-ACA], indicating an enhanced mechanical property by mixing the pure enantiomers in both single crystals and cocrystals. It should also be noted that cocrystallization improved the mechanical properties of single crystals, probably due to the stronger supramolecular organization in the cocrystals mediated through the combination of hydrogen bonding and π-π stacking, resulting in rigidity orders of [BPE/ D-ACA > D-AcA > BPE], [BPE/L-ACA > L-AcA > BPE], and [BPE/DL-ACA > DL-ACA > BPE].

Figure 5.

Figure 5

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(a, b, g and h) AFM images of topographic modulus maps of (a) D-AcA, (b) DL-ACA, (g) D-AcA/BPE, and (h) DL-ACA/BPE. Scale bar is 2 μm. (c, d, i and j) Statistical Young’s moduli distributions of (c) D-AcA, (d) DL-ACA, (i) D-AcA/BPE, and (j) DL-ACA/BPE. (e, f, k and l) Statistical point stiffness distributions of (e) D-AcA, (f) DL-AcA, (k) D-AcA/BPE, and (l) DL-ACA/BPE.

Photo-induced emission of BPE based crystals

As a photochromic stilbene derivative with enhanced fluorescence during trans-cis transition, the incorporation of BPE into soft gel materials was recently explored for fluorescent imprinting [48]. However, the photo-responsiveness of BPE in the solid-state is still low, raising an urgent need to improve the efficiency of photo-induced emission for fluorescence printable solid materials. Due to the observed different supramolecular crystal packing of BPE, we further evaluated the in situ UV light sensitivity of BPE-based single and cocrystals using fluorescence microscopy. Before UV light irradiation, all crystals showed a weak green emission (Fig. 6a-c and Fig. S25c). Significantly enhanced fluorescence was imprinted for both BPE/D-AcA and BPE/L-ACA within 60 s UV light irradiation (Fig. 6a and Fig. S25c). Photo-induced trans-cis isomerization resulted in a slight morphology change on the surface of the crystals, as detected in the bright-field microscopy images (Fig. S25a and b). However, it BPE/DL-ACA required a longer duration of 300 s to achieve a significant fluorescence imprint, indicating lower photo-responsiveness of racemic BPE/DL-AcA compared to the enantiopure BPE/D-ACA and BPE/L-ACA crystals (Fig. 6b). A slight surface change was also observed for BPE/DL-AcA crystals during the UV irradiation (Fig. S25d). As a control, BPE single crystals did not show any enhanced fluorescence after 300 s of UV irradiation and no change was observed in the crystal surface, which suggested negligible photo-responsiveness of BPE single crystals (Fig. 6c and Fig. S25e). Therefore, the sequence of UV light sensitivity is [BPE/(D or L)-ACA > BPE/DL-ACA > BPE], which may reflect the AcA coformer creating the more ordered π-π stacking of BPE: single crystal structures demonstrate the π-π interactions order to be [BPE/(D or L)-ACA > BPE/DL-ACA > BPE] (Fig. 4c, g and i). The stronger π-π interactions between BPE molecules promote the ability of BPE to absorb UV light, inducing higher photosensitivity. The proof of concept was further validated for fluorescent imprinting of BPE/L-AcA crystals before and after UV irradiation in a specific region (Fig. 6d and e, red circle). No fluorescence was observed before UV light irradiation, and strong fluorescence could be imprinted only in the specific region irradiated with UV light. These results suggest that the photoinduced enhanced emission of BPE-based cocrystals holds potential applications as solid-state dopant for fluorescence printable supramolecular materials.

Figure 6.

Figure 6

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Temporal analysis of UV light-responsive properties and enhanced fluorescence of BPE based crystals. (a) L-AcA/BPE, (b) DL-ACA/BPE, and (c) BPE. (d and e) Photo imprint of L-ACA/BPE crystals before (d) and after (e) 60 s of UV irradiation. Scale bar is 100 pm.

Piezoelectricity of the single and cocrystals

Non-centrosymmetric crystal symmetries with different packing networks produce different piezoelectric responses due to the varying supramolecular polarization and stiffness. We further explored the piezoelectric properties of the single crystals and cocrystals by density-functional theory (DFT) calculations. The results of the predicted piezoelectric responses are summarized in Table 1 and detailed in Tables S4-8. Both the racemic DL-ACA single crystal and the racemic BPE/DL-AcA cocrystal belong to centrosymmetric space groups (P21/c and P2/n), and accordingly are non-piezoelectric (all tensor values = 0). To date, only two racemic amino acids have been shown to demonstrate piezoelectricity, DL-Alanine, and DL-Tyrosine. DL-Alanine has a longitudinal piezoresponse of 10 pC/N confirmed by PFM, and a maximum predicted shear response of 18 pC/N from DFT calculations [44]. DL-Tyrosine has been shown to exhibit some degree of electromechanical coupling but the size of its response has yet to be quantified [51]. Of the three single crystal components (BPE, L-AcA, and D-AcA), the highest-magnitude predicted piezoelectric strain constant was the d24 value of BPE, 10.9 pC/N. However, both enantiopure cocrystals of BPE/L-AcA and BPE/D-AcA were predicted to demonstrate significantly larger piezoelectric responses, with maximum strain constants of 34.9 pC/N and 22.9 pC/N, respectively. The predicted maximum response of BPE/L-AcA is over twice that of the recently reported BPY/L-AcA single crystal (15 pC/N) [52] and half that of engineered, highly aromatic peptide crystals (73 pC/N) [53]. The porous structure of both BPE/L-AcA and BPE/D-AcA cocrystals (Fig. S26) gives rise to high longitudinal stiffness in the direction of the continuous pore walls along the a axis, but this coincides with low shear stiffness values. Low stiffness corresponds to high piezoelectric response as it facilitates more ionic displacement per unit force. There is a gap along the b axis between the two porous layers in the unit cell, which is stabilized by water molecules during crystallization and can be easily closed by applying a force in the 2 direction. While the piezoelectric response of the BPE single crystal is comparable to biological materials such as viruses and glycine assemblies, the predicted piezoelectric strain constants of BPE/L-AcA and BPE/D-AcA are comparable to the poled inorganic polymer polyvinylidene fluoride (PVDF). A full comparison of different biological and non-biological materials is presented in Table S9. We further investigated the dielectric properties of the piezoelectric crystals (Table S10). The cocrystals show a small increase in relative permittivity, rising from 3.3 to 4.0 for single crystals to 4.8 to 5.0 for cocrystals. The cocrystals showed significant predicted voltage constants, with maximum values of 567 and 623 mV m/N for BPE/L-ACA and BPE/D-ACA, respectively, indicating their potential for energy harvesting applications. These values are 2-fold higher than that of traditional Lead Zirconium Titanate (PZT) ceramics (gmax = 250 - mV m/N) [54], the most widely exploited piezoelectric materials used for sensing and actuation. Overall, the DFT calculations confirm that in both the single crystals and cocrystals, the pure L- and D-forms have nearly identical material properties. However, cocrystallization of BPE with a pure isomer (either L- or D-forms) significantly increases the predicted piezoelectric response, whereas the racemic mixtures generate centrosymmetric space groups that preclude piezoelectricity.

Conclusion

In summary, we have explored the effect of enantiopure and racemic amino acids on the properties of both single crystals and cocrystals produced with a nonchiral coformer. The chirality of amino acids affects the directionality and specificity of supramolecular organization, leading to different packing modes that regulate the physical properties of crystals. The supramolecular structures of the enantiopure crystals show nearly identical packing modes and similar properties, including mechanical stiffness, photo-sensitivity, and piezoelectricity. However, the racemic mixtures formed completely different crystal packing modes compared to those of the enantiopure ones. In this study, BPE/DL-ACA crystals show the highest rigidity with a Young’s modulus of 53.4 GPa, while BPE/D-ACA and BPE/L-ACA crystals exhibited higher efficiency of photo-induced emission and higher predicted piezoelectric coefficients and voltage constants. Cocrystallization with BPE induces morphology transition, enhanced supramolecular chirality, improved thermal stability and increased mechanical strength of the AcA crystals. This work demonstrates the systematic modulation of the macroscopic properties of organic crystals by rational selection of the chirality of amino acids in both single crystals and cocrystals with nonchiral coformers, which holds great potential as attractive functional elements for the reinforcement of composite materials, fluorescent imprinting, and energy harvesting.

Supplementary Material

Supplementary material

Table 1. Calculated piezoelectric strain components dik (pC/N) of single and cocrystals.

Crystal d 14 d 15 d 24 d 25 d 31 d 32 d 33 d 36
L-AcA 1.3 0 0 2.1 0 0 0 2.9
D-AcA 5.3 0 0 1.2 0 0 0 1.3
DL-ACA 0 0 0 0 0 0 0 0
BPE 0 4.2 10.9 0 2.6 1.7 0.4 0
BPE/L-ACA 34.9 0 0 1.9 0 0 0 17.4
BPE/D-ACA 7.7 0 0 1.8 0 0 0 22.9
BPE/DL-ACA 0 0 0 0 0 0 0 0
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Acknowledgments

This work was supported by the European Research Council under the European Union Horizon 2020 research and innovation program (no. 694426) (E.G.), Science Foundation Ireland (SFI) under awards number 15/CDA/3491 and 12/RC/2275 (D. T.) and supercomputing resources to S.G. and D.T. at the SFI/ Higher Education Authority Irish Center for High-End Computing (ICHEC), National Natural Science Foundation of China (No. 11804148) (B. X.), Natural Science Foundation of Jiangsu province (No. BK20180320) (B. X.), and the Fundamental Research Funds for the Central Universities (No. 020414380118) (B. X.). The authors thank Dr. Sigal Rencus- Lazar for language editing assistance.

Footnotes

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contributions

W. Ji, B. Xue, S. Bera contributed equally to this work. W. Ji and E. Gazit conceived and designed the work;W. Ji conducted the experiments of crystal preparation, fluorescence images, CD study, PXRD, FTIR, and NMR;B. Xue, Y. Cao, and W. Wang conducted the experiments of mechanical properties of crystals; L. J. W. Shimon measured the crystal structures;S. Bera analyzed the crystal structures;S. Guerin, S. A.M. Tofail, and D. Thompson calculated the piezoelectric tensors of the crystals; Q. Ma conducted the TGA experiments;W. Ji, S. Bera, B. Xue and E. Gazit co-wrote the manuscript. All authors discussed and commented on the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Data availability

Data are available in the Supplementary Information or from the corresponding author upon request. The X-ray crystallographic data for structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 1994775, 1994776, 1994780, 1994777, 1994778, and 1994779 for D-ACA, DL-ACA, BPE, BPE/L-ACA, BPE/ D-ACA, and BPE/DL-ACA, respectively. The data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

References

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material
EMS117036-supplement-Supplementary_material.pdf (3.6MB, pdf)

Data Availability Statement

Data are available in the Supplementary Information or from the corresponding author upon request. The X-ray crystallographic data for structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 1994775, 1994776, 1994780, 1994777, 1994778, and 1994779 for D-ACA, DL-ACA, BPE, BPE/L-ACA, BPE/ D-ACA, and BPE/DL-ACA, respectively. The data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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